Incidence and risk of periodontitis in obstructive sleep apnea: A meta-analysis

Introduction At present, the possible relationship between obstructive sleep apnea and periodontitis has been reported. The link remains ambiguous and unclear. The objective of this study is to assess the association between OSA and periodontitis. Methods Three databases, including Pubmed, Embase, and the Web of Science, were systematically searched to identify eligible studies that from their establishment to February 2022 for relevant studies. Subsequently, a meta-analysis was conducted to determine the relationship of pooled-effects more accurately. Results A summary analysis of the 9 results from the studies covering 43,414 individuals showed a statistical association results of the between OSA and the incidence rate of periodontitis(OR = 0.52; 95% CI: 0.49–0.55; I2 = 98.43%; P = 0.000). In addition, OSA patients and the risk of the population were statistically significantly associated with an increased risk of periodontitis.(OR = 1.56; 95% CI: 1.06–2.06; P = 0.00). Conclusions Our results indicated that OSA may be associated with an increased risk of periodontitis. Further studies are required to confirm the link and explore the underlying mechanism of the link.

a1111111111 a1111111111 a1111111111 a1111111111 a1111111111 Introduction 1. case-control, cross-sectional, cohort study 2. investigation into the association of OSA with risk of periodontitis 3. The incidence rate of periodontitis in OSA patients is calculated 4. (Age�18 years) studies were included 5. Case reports, case series, or cohort studies with <20 patients were excluded. Also excluded were case reports, reviews, books, abstracts, and editorials OSA was defined as a diagnosed paroxysmal sleep apnea syndrome that has met the conditions of providing a clear auxiliary clinical diagnosis and excluded patients with only a single diagnosis of snoring, sleep disorders, or sleep disorders.
Considering that various studies are inconsistent in the diagnosis of OSA, we mainly refer to overnight polysomnography or home sleep testing monitor-Apnea Risk Evaluation System (ARES) as the main diagnostic index. Nevertheless, we also recognize the potential importance of various clinical scales for OSA risk assessment and chose the Epworth Sleeping Score (ESS) and Berlin Questionnaire as the secondary outcome measures to provide additional insight into the association of OSA with periodontitis. we included the study with the longest followup or largest number of participants when more than 1 article reported data from 1 cohort or 1 health data-base. Without providing an odd-risk (OR) estimate with a corresponding 95% confidence interval (CI),were excluded from this study. The data was extracted by at least two independent investigators.
In the first stage, all potentially relevant articles were reviewed by two independent reviewers by reading titles and abstracts to decide the eligibility of studies. The full text that exclusion of non-eligible studies disagreements was obtained and assessed independently. All data were rechecked for internal consistency, if necessary, any disagreements were resolved by discussion and consultation with the third author of the review.

Search strategy
We systematically conducted a search of the literature using the PubMed, Embase, and Web of Science databases from their establishment to February 2022 for relevant studies. A detailed and complete retrieval strategy using Obstructive Sleep Apnea, Obstructive Sleep Apnea Syndrome, Periodontitis, and periodontal disease. as the keywords is shown in S1 Table in Supplement. Additionally, in order to find other relevant articles that were not retrieved according to the search formula in the public database, we conducted a manual search of references in the included studies and of relevant reviews.

Data extraction and quality assessment
Where possible, we extracted data on the exposures population source, study design, sample size, gender distribution, mean age and age range of study participants, and summary-level incidence of OSA and Periodontitis.
The quality of the selected papers was assessed based on the Newcastle-Ottawa scale (NOS) that has been recently recommended by systematic review practice guidelines as the most reliable instrument for conducting quality assessment of cross-sectional or cohort studies in systematic reviews. Studies with a score of points by NOS were classified as low quality (0-3 points), medium quality (4-6 points), and high quality (�7points).
Studies with a score of 0-3 points were classified as low quality, with a score of 4-6 points were classified as medium quality, and �7 points were classified as high quality.

Statistical analysis
The OR and corresponding 95%CI were extracted from each study and used to assess an association between OSA and Periodontitis. A priori, random-effects meta-analysis and metaregression were used to quantify this heterogeneity based on previous meta-analyses [25], and we anticipated high levels of heterogeneity. We used A chi-square (X 2 ) test and I-squared (I 2 ) statistic to evaluate heterogeneity among included studies. Statistical heterogeneity was considered significant when p < 0.10 for X 2 test or I 2 > 50% [28]. Egger's regression test16 [29] and Begg's test [30] were used to statistically assess publication bias. The funnel plot was visually inspected to confirm publication bias, and we performed a sensitivity analysis by excluding one study each time and rerunning the analysis to verify the robustness of the overall results. (P<0.05 was considered statistically significant) conclusions were based on the use of Stata software version 16.0 (Stata Corp., College Station, Texas, US).

Retrieved literatures
In our database, we retrieved 472 research-related literatures. Eight articles were included in this meta-analysis, including seven cohort studies and two case-control studies. This study selection process is shown in

PLOS ONE
Review of periodontitis among patients with heart obstructive sleep apnea

Quality assessment
Six articles [32][33][34][36][37][38] were considered to be of high quality and three [31,35,39] of fair quality based on the quality assessment of NOS scores. The specific assessment of NOS scores for these 9 studies is shown in Table 2.

The incidence of periodontitis in OSA
A total of 8 articles [31][32][33][34][35][36][37][38] that analyzed the prevalence of periodontitis in patients with OSA were included in our study. The eight articles, as shown (OR = 0.33; 95% CI: 0.32-0.33; P = 0.000; I 2 = 98.56%) in Fig 2, describe the incidence rate of periodontitis in OSA risk patients by using dichotomous variables. Due to the high heterogeneity, we performed sensitivity analysis on the studies by sensitivity analysis was carried out by removing trials one by one to identify the heterogeneity, whether the source of the results were driven by a single study with large sample sizes. Two studies [31,32] with large sample sizes were excluded in order to reduce heterogeneity. After excluding two literatures, the inclusion study had no significant effect on OR and 95% CI(OR = 0.52; 95% CI: 0.49-0.55; I 2 = 98.43%; P = 0.000).

OSA and risk of all-cause periodontitis
Six articles [31,32,34,35,38,39] included in the study evaluated the relationship between OSA and periodontitis. In total, a history of OSA is associated with an increased risk of periodontitis. These studies reported OSA and the risk of periodontitis. The summary results showed that OSA was associated with an increased risk of periodontitis (OR = 1.56; 95% CI: 1.06-2.06; The Newcastle-Ottawa Quality Assessment Scale (NOS) (Stang, et al., 2010) was used to assess the quality of the included studies in three aspects, selection, comparison and results. The scores of cohort studies and case-control studies ranged from 0 to 9 and the higher the score, the higher the research quality. NOS scores � 7, 4-6 and 0-3 represent high, medium and low quality, respectively. https://doi.org/10.1371/journal.pone.0271738.t002

PLOS ONE
I 2 = 90.4%; P = 0.000; Fig 5), but with considerable heterogeneity across studies. It has been suggested that the origin of this heterogeneity cannot be explained by sample size (large or small) subgroup analysis or by study design (prospective or retrospective) analyses performed by omitting one individual study sequentially, as none of the studies had a significant impact on the pooled OR and 95%CI (Fig 6), and it has been suggested that the research results are  reliable. According to a visual inspection of the funnel plot analysis result, no evidence had a significant effect of publication bias (Fig 7).

Discussion
By conducting this meta-analysis that based on 9 studies in 43,414 individuals, we performed to demonstrate the association between OSA and the future risk of Periodontitis and verified, updated, and extended a previous meta-analysis [25]. In the past, no analysis has been conducted to assess the relationship between the two by evaluating the incidence rate of Periodontitis in OSA. We believe that OSA may be a potential risk indicator for periodontitis. Our conclusion reached above is supported by results from 2 other large population-based studies. Sanders et al. [32] screened individuals from four cities with large Hispanic/Latino populations in the U.S. between 2008 and 2011 and found that patients diagnosed with OSA were more likely to develop periodontitis and a certain dose-response relationship between them has been determined. When the AHI � 15, the crude probability of severe periodontitis is about 7 times higher than that of AHI 0.0 (OR = 6.9, 95% Cl: 4.8, 10.0). Seo et al. [35] analyzed 3 years of follow-up data based on the Korean Genome and Epidemiology Study (KoGES), and suggested that a statistically significant correlation between OSA and periodontal risk(OR = 1.84, 95% Cl: 1.18, 2.87) after adjusting for gender, body mass index, smoking, drinking, snoring, mouth breathing, and diabetes during sleep. All these findings indicate that OSA might be a potential predictor for Periodontitis. At present, few or no meta-analyses have been conducted to confirm the relationship between OSA and periodontitis from the incidence rate. Our current meta-analysis, which included the results of 9 studies, found that the prevalence of periodontitis in patients with OSA was significantly higher than that in patients without OSA (OR = 0.52; 95% CI: 0.49-0.55; I 2 = 98.43%; P = 0.000). However, owing to the risk of bias, the results of this meta-systematic should be interpreted with caution. First, diagnostic criteria from different studies that were included in this meta-systematic for OSA and periodontitis could be varied. Second, some studies have conducted hierarchical research based on AHI for OSA, while others only distinguish OSA patients from non-OSA patients without hierarchical research, which has a negative impact on data extraction and result comparison. The supplied data comes from a variety of sources, some of which could originate from the clinical retrospective studies and others from public databases, which may also be an explanation for the existence of a risk of bias. Currently, relatively few studies with uniform diagnostic standards have reported the association between OSA and periodontitis according to the incidence rate. More studies should be needed to further confirm this association.
The pathological association between periodontitis and OSA is still unclear. Although Al-Jewair et al. [25] found a statistically significant correlation between periodontal disease and OSA in a previous meta-analysis, the causal relationship between them is still controversial. However, several conclusions have been put forward to explain this relationship at present. Intermittent hypoxemia causes anoxia / reperfusion injury in OSA patients, which contributes to increased production of active oxidants and oxygen radicals and leads to the formation of other systemic inflammatory mediators in various ways, which may be the potential source of local or systemic inflammation in OSA [40].
The risk of periodontitis for patients with OSA also increases with the increase of this serum inflammatory mediator, and based on the decrease of oxygen saturation in patients with OSA, may lead to systemic inflammatory changes, including periodontal tissue [41]. It is often observed that oral breathing makes the oral mucosa dry in OSA patients, which may increase the risk of bacterial colonization and lead to higher plaque values and further increase the risk of periodontal disease [33,34].
Interestingly, periodontitis-induced systemic inflammatory responses involve systemic increases in acute-phase reactants and activated pro-inflammatory cytokines that are resident in the immune system [42], and oxidative stress is also involved in this inflammatory pathway [43]. We speculated that this similar phenomenon of oxidative stress and systemic inflammation may also be attributed to the correlation between OSA and periodontitis. In addition, the common risk factors and complications of OSA and periodontitis have also been shown to be exceedingly similar in some studies [36].
To the best of our knowledge, the present meta-analysis is the first that attempts to assess and summarize the relationship between OSA and periodontitis risk from the perspective of incidence rate and updates the previous studies of Al-Jewair et al [25] from the perspective of risk factors. Sensitivity analysis has indicated the stability of the main results. Nevertheless, the results of the present meta-analysis are subject to several limitations that should be considered with a rigorous attitude. In various studies, different criteria were used for the diagnosis of OSA and periodontitis. This may affect the selection of sample group and make the included studies show heterogeneity that exists between individual studies and may restrict our final conclusions. Additionally, at present, the number of only 9 studies eligible for inclusion was small in this meta-analysis. This study did not systematically discuss the relationship between OSA and periodontitis from the perspective of dose-response or cause-effect. The results and conclusions of this meta-analysis were only preliminary and require further analysis, which will necessitate more research results on the relationship between OSA and periodontitis. Even so, despite these limitations, our analysis still has extraordinarily significant significance. This study reveals a potential association between periodontitis and OSA, contributing to identifying the susceptible group of periodontitis or periodontal disease. Further exploration of the mechanism of the association between OSA and periodontitis is required, which may enable to provide new strategies for the treatment and prevention of periodontitis.

Conclusions
Our present study finds that a relationship exists between OSA and periodontitis. However, published data on the relationship between OSA and periodontitis is still insufficient. Further studies are needed to understand the underlying mechanisms of association, especially studies demonstrating the link between dose-response and cause-effect.